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  • 1
    Keywords: RECEPTOR ; CANCER ; POPULATION ; RISK ; SITE ; DISTINCT ; GENE ; GENES ; GENOME ; RESOLUTION ; BINDING ; SEQUENCE ; ASSOCIATION ; SUSCEPTIBILITY ; SUSCEPTIBILITY LOCUS ; ALPHA ; BREAST ; breast cancer ; BREAST-CANCER ; genetics ; SNP ; POPULATIONS ; PROJECT ; ESTROGEN-RECEPTOR ; HETEROGENEITY ; ORIGIN ; TAMOXIFEN ; ASSOCIATIONS ; SNPs ; SCIENCE ; ESTROGEN ; HAPLOTYPE ; LOCUS ; TRAITS ; estrogen receptor ; BINDING-SITE ; CHINESE POPULATION ; GENOME-WIDE ASSOCIATION ; AFRICAN-AMERICAN ; ESTROGEN-RECEPTOR-ALPHA ; CONFER SUSCEPTIBILITY ; BINDING SITE ; Genetic ; COMMON VARIANTS ; ANCESTRY ; PANEL ; CAUSAL VARIANTS
    Abstract: We used an approach that we term ancestry-shift refinement mapping to investigate an association, originally discovered in a GWAS of a Chinese population, between rs2046210[T] and breast cancer susceptibility. The locus is on 6q25.1 in proximity to the C6orf97 and estrogen receptor alpha (ESR1) genes. We identified a panel of SNPs that are correlated with rs2046210 in Chinese, but not necessarily so in other ancestral populations, and genotyped them in breast cancer case: control samples of Asian, European, and African origin, a total of 10,176 cases and 13,286 controls. We found that rs2046210[T] does not confer substantial risk of breast cancer in Europeans and Africans (OR = 1.04, P = 0.099, and OR = 0.98, P = 0.77, respectively). Rather, in those ancestries, an association signal arises from a group of less common SNPs typified by rs9397435. The rs9397435[G] allele was found to confer risk of breast cancer in European (OR = 1.15, P = 1.2x10(-3)), African (OR = 1.35, P = 0.014), and Asian (OR = 1.23, P = 2.9x10(-4)) population samples. Combined over all ancestries, the OR was 1.19 (P = 3.9x10(-7)), was without significant heterogeneity between ancestries (P-het = 0.36) and the SNP fully accounted for the association signal in each ancestry. Haplotypes bearing rs9397435[G] are well tagged by rs2046210[ T] only in Asians. The rs9397435[G] allele showed associations with both estrogen receptor positive and estrogen receptor negative breast cancer. Using early-draft data from the 1,000 Genomes project, we found that the risk allele of a novel SNP (rs77275268), which is closely correlated with rs9397435, disrupts a partially methylated CpG sequence within a known CTCF binding site. These studies demonstrate that shifting the analysis among ancestral populations can provide valuable resolution in association mapping
    Type of Publication: Journal article published
    PubMed ID: 20661439
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  • 2
    Abstract: PURPOSE: Women diagnosed with breast cancer have heterogeneous survival outcomes that cannot be fully explained by known prognostic factors, and germline variation is a plausible but unconfirmed risk factor. METHODS: We used three approaches to test the hypothesis that germline variation drives some differences in survival: mortality loci identification, tumor aggressiveness loci identification, and whole-genome prediction. The 2954 study participants were women diagnosed with breast cancer before age 50, with a median follow-up of 15 years who were genotyped on an exome array. We first searched for loci in gene regions that were associated with all-cause mortality. We next searched for loci in gene regions associated with five histopathological characteristics related to tumor aggressiveness. Last, we also predicted 10-year all-cause mortality on a subset of 1903 participants (3,245,343 variants after imputation) using whole-genome prediction methods. RESULTS: No risk loci for mortality or tumor aggressiveness were identified. This null result persisted when restricting to women with estrogen receptor-positive tumors, when examining suggestive loci in an independent study, and when restricting to previously published risk loci. Additionally, the whole-genome prediction model also found no evidence to support an association. CONCLUSION: Despite multiple complementary approaches, our study found no evidence that mortality in women with early onset breast cancer is influenced by germline variation.
    Type of Publication: Journal article published
    PubMed ID: 28503721
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  • 3
    Abstract: Purpose BRCA1/2 mutations increase the risk of breast and prostate cancer in men. Common genetic variants modify cancer risks for female carriers of BRCA1/2 mutations. We investigated-for the first time to our knowledge-associations of common genetic variants with breast and prostate cancer risks for male carriers of BRCA1/ 2 mutations and implications for cancer risk prediction. Materials and Methods We genotyped 1,802 male carriers of BRCA1/2 mutations from the Consortium of Investigators of Modifiers of BRCA1/2 by using the custom Illumina OncoArray. We investigated the combined effects of established breast and prostate cancer susceptibility variants on cancer risks for male carriers of BRCA1/2 mutations by constructing weighted polygenic risk scores (PRSs) using published effect estimates as weights. Results In male carriers of BRCA1/2 mutations, PRS that was based on 88 female breast cancer susceptibility variants was associated with breast cancer risk (odds ratio per standard deviation of PRS, 1.36; 95% CI, 1.19 to 1.56; P = 8.6 x 10-6). Similarly, PRS that was based on 103 prostate cancer susceptibility variants was associated with prostate cancer risk (odds ratio per SD of PRS, 1.56; 95% CI, 1.35 to 1.81; P = 3.2 x 10-9). Large differences in absolute cancer risks were observed at the extremes of the PRS distribution. For example, prostate cancer risk by age 80 years at the 5th and 95th percentiles of the PRS varies from 7% to 26% for carriers of BRCA1 mutations and from 19% to 61% for carriers of BRCA2 mutations, respectively. Conclusion PRSs may provide informative cancer risk stratification for male carriers of BRCA1/2 mutations that might enable these men and their physicians to make informed decisions on the type and timing of breast and prostate cancer risk management.
    Type of Publication: Journal article published
    PubMed ID: 28448241
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  • 4
    Abstract: The prevalence and spectrum of germline mutations in BRCA1 and BRCA2 have been reported in single populations, with the majority of reports focused on White in Europe and North America. The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) has assembled data on 18,435 families with BRCA1 mutations and 11,351 families with BRCA2 mutations ascertained from 69 centers in 49 countries on six continents. This study comprehensively describes the characteristics of the 1,650 unique BRCA1 and 1,731 unique BRCA2 deleterious (disease-associated) mutations identified in the CIMBA database. We observed substantial variation in mutation type and frequency by geographical region and race/ethnicity. In addition to known founder mutations, mutations of relatively high frequency were identified in specific racial/ethnic or geographic groups that may reflect founder mutations and which could be used in targeted (panel) first pass genotyping for specific populations. Knowledge of the population-specific mutational spectrum in BRCA1 and BRCA2 could inform efficient strategies for genetic testing and may justify a more broad-based oncogenetic testing in some populations.
    Type of Publication: Journal article published
    PubMed ID: 29446198
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  • 5
    Electronic Resource
    Electronic Resource
    [S.l.] : American Institute of Physics (AIP)
    Journal of Applied Physics 89 (2001), S. 7634-7636 
    ISSN: 1089-7550
    Source: AIP Digital Archive
    Topics: Physics
    Notes: Measurements of the magnetic susceptibility χ, specific heat C, and thermoelectric power S were carried out for the solid solution Ce(NixPd1−x)2Si2 (0≤x≤1). With increasing x, the ground state changes from an antiferromagnetic Kondo state (x〈0.2) to an intermediate valence state (x〉0.3). The heavy fermion state was found to evolve at the crossover concentration at x=0.2, where the long-range magnetic order seems to disappear. © 2001 American Institute of Physics.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1089-7550
    Source: AIP Digital Archive
    Topics: Physics
    Notes: We have developed a substrate biased plasma enhanced chemical vapor deposition technique to fill high aspect ratio submicron gap in first metal contact layer. In this technique, active ion deposition from tetraethylorthosilicate and oxygen and ion bombardment from oxygen and argon ions occurred concurrently to fill 0.5 μm height/0.5 μm space aluminum patterns on silicon wafer without forming soft spots and keyholes. The effects of argon ions to the modification of surface topography are discussed. The deposited films have a low residual stress (〈 −3 × 109 dyne/cm2) and wet etching rate. The properties of the deposited films have been evaluated by infrared spectroscopy and triangular voltage sweeping technique.
    Type of Medium: Electronic Resource
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  • 7
    Publication Date: 2018-01-09
    Description: Background: Pancreatic cancer mutation signatures closely resemble breast cancer, suggesting that both cancers may have common predisposition mechanisms that may include commonly inherited SNPs. Methods: We examined 23 genetic variants known to be associated with pancreatic cancer as breast cancer risk factors in the Root genome-wide association study (GWAS; 1,657 cases and 2,029 controls of African diaspora) and GAME-ON/DRIVE GWAS (16,003 cases and 41,335 controls of European ancestry). Results: None of the pancreatic cancer susceptibility variants were individually associated with breast cancer risk after adjustment for multiple testing (at α = 0.002) in the two populations. In Root GWAS, a change by one SD in the polygenic risk score (PRS) was not significantly associated with breast cancer. In addition, we did not observe a trend in the relationship between PRS percentiles and breast cancer risk. Conclusions: The association between reported pancreatic cancer genetic susceptibility variants and breast cancer development in women of African or European ancestry is likely weak, if it does exist. Impact: Known GWAS-derived susceptibility variants of pancreatic cancer do not explain its shared genetic etiology with breast cancer. Cancer Epidemiol Biomarkers Prev; 27(1); 116–8. ©2017 AACR .
    Print ISSN: 1055-9965
    Electronic ISSN: 1538-7755
    Topics: Medicine
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  • 8
    Publication Date: 2018-09-05
    Description: Background: Although germline genetics influences breast cancer incidence, published research only explains approximately half of the expected association. Moreover, the accuracy of prediction models remains low. For women who develop breast cancer early, the genetic architecture is less established. Methods: To identify loci associated with early-onset breast cancer, gene-based tests were carried out using exome array data from 3,479 women with breast cancer diagnosed before age 50 and 973 age-matched controls. Replication was undertaken in a population that developed breast cancer at all ages of onset. Results: Three gene regions were associated with breast cancer incidence: FGFR2 ( P = 1.23 x 10 –5 ; replication P 〈 1.00 x 10 –6 ), NEK10 ( P = 3.57 x 10 –4 ; replication P 〈 1.00 x 10 –6 ), and SIVA1 ( P = 5.49 x 10 –4 ; replication P 〈 1.00 x 10 –6 ). Of the 151 gene regions reported in previous literature, 19 (12.5%) showed evidence of association ( P 〈 0.05) with the risk of early-onset breast cancer in the early-onset population. To predict incidence, whole-genome prediction was implemented on a subset of 3,076 participants who were additionally genotyped on a genome wide array. The whole-genome prediction outperformed a polygenic risk score [AUC, 0.636; 95% confidence interval (CI), 0.614–0.659 compared with 0.601; 95% CI, 0.578–0.623], and when combined with known epidemiologic risk factors, the AUC rose to 0.662 (95% CI, 0.640–0.684). Conclusions: This research supports a role for variation within FGFR2 and NEK10 in breast cancer incidence, and suggests SIVA1 as a novel risk locus. Impact: This analysis supports a shared genetic etiology between women with early- and late-onset breast cancer, and suggests whole-genome data can improve risk assessment. Cancer Epidemiol Biomarkers Prev; 27(9); 1057–64. ©2018 AACR .
    Print ISSN: 1055-9965
    Electronic ISSN: 1538-7755
    Topics: Medicine
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  • 9
    Publication Date: 2018-06-02
    Description: Background: Risk prediction models have been widely used to identify women at higher risk of breast cancer. We aimed to develop a model for absolute breast cancer risk prediction for Nigerian women. Methods: A total of 1,811 breast cancer cases and 2,225 controls from the Nigerian Breast Cancer Study (NBCS, 1998–2015) were included. Subjects were randomly divided into the training and validation sets. Incorporating local incidence rates, multivariable logistic regressions were used to develop the model. Results: The NBCS model included age, age at menarche, parity, duration of breastfeeding, family history of breast cancer, height, body mass index, benign breast diseases, and alcohol consumption. The model developed in the training set performed well in the validation set. The discriminating accuracy of the NBCS model [area under ROC curve (AUC) = 0.703, 95% confidence interval (CI), 0.687–0.719] was better than the Black Women's Health Study (BWHS) model (AUC = 0.605; 95% CI, 0.586–0.624), Gail model for white population (AUC = 0.551; 95% CI, 0.531–0.571), and Gail model for black population (AUC = 0.545; 95% CI, 0.525–0.565). Compared with the BWHS and two Gail models, the net reclassification improvement of the NBCS model were 8.26%, 13.45%, and 14.19%, respectively. Conclusions: We have developed a breast cancer risk prediction model specific to women in Nigeria, which provides a promising and indispensable tool to identify women in need of breast cancer early detection in Sub-Saharan Africa populations. Impact: Our model is the first breast cancer risk prediction model in Africa. It can be used to identify women at high risk for breast cancer screening. Cancer Epidemiol Biomarkers Prev; 27(6); 636–43. ©2018 AACR .
    Print ISSN: 1055-9965
    Electronic ISSN: 1538-7755
    Topics: Medicine
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